Folinic Acid Enhanced Cytotoxicity of Fluoropyrimidines In Human Breast Cancer Cells
This report describes the effects of the natural diastereoisomer of 5-formyltetrahydrofolate (6S)- and of the mixture of both the natural and unnatural diastereoisomers (6RS)-5-HCO-H4PteGlu (folinate) on the cytotoxicity of 5-fluoro-2′-deoxyuridine (FdUrd) and 5-fluorouracil (FUra) in MCF-7 and MDA-...
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| Format: | Article |
| Language: | English |
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De Gruyter
1993-02-01
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| Series: | Pteridines |
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| Online Access: | https://doi.org/10.1515/pteridines.1993.4.1.51 |
| Summary: | This report describes the effects of the natural diastereoisomer of 5-formyltetrahydrofolate (6S)- and of the mixture of both the natural and unnatural diastereoisomers (6RS)-5-HCO-H4PteGlu (folinate) on the cytotoxicity of 5-fluoro-2′-deoxyuridine (FdUrd) and 5-fluorouracil (FUra) in MCF-7 and MDA-MB 231. human breast cancer cell lines. Continuous exposure of exponentially growing cells to various concentrations of FUra for 72 h caused a 50% inhibition of growth with lC50 at concentrations of 3.40± 0.16 and 29± 1.40 11M in MCF-7 and MDA-MB 231. respectively. Preincubation of the cells for 24 h with (6S)-5-CHO-H4PteGlu (5 µM) prior to addition of FUra decreased the IC50 values by 2.4-2.6-fold in both cell lines. A quantitatively similar effect was achieved by preincubation with ]() µM of (6RS)-5-HCO-H4PteGlu. The cytotoxicity of FdUrd was markedly more pronounced than that of FUra exhibiting IC50, values at a range of 0.045- 0.050 µM for both cell lines. Preincubation with (6S)-5-HCO-H4PteGlu increased the susceptibility to the drug by about 3.5-fold. The optimal dose of (6S)-5-CHO-H4PteGlu for achieving the lowest IC50 value for FdURd in MCF-7 cells was 5 µM. whereas that in MDA-MB 231 was 20 µM. Similar increase of the cytotoxicity of FdUrd was obtained with about a 2-fold higher concentration of (6RS)-5-HCO-H4PteGlu. Cells pretreated lor 24 h with FUra or FdUrd respectively. exhibited enhanced incorporation of [3H] thymidine into the TCA-precipitable fraction . Presence of (6S)-5-HCO-H4PteGlu (10 µM) doubled the amount of incorporated thymidine. which reflects depletion of intracellular thymidylate pools due to enhanced formation and stabilization of the complex formed between thymidylate synthase. flouorodeoxydylate and 5.1.0-methylenetetrahydrofolate. |
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| ISSN: | 0933-4807 2195-4720 |